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  • C07D487/04—Ortho-condensed systems

Definitions

• the present invention relates to a novel pyrazine derivative and a salt thereof, which are useful as medicaments.
• Adenosine is a ubiquitous biochemical messenger. Adenosine binds to and activates seven-transmembrane spanning G-protein coupled receptors, eliciting a variety of physiological responses. Adenosine receptors are divided into four known subtypes (i.e., A 1 , A 2a , A 2b , and A 3 ). These receptor subtypes mediate different, and sometimes opposing, effects. Activation of the adenosine A 1 receptor, for example, elicits an increase in renal vascular resistance, while activation of the adenosine A 2a receptor elicits a decrease in renal vascular resistance. Accordingly, adenosine antagonists are useful in the prevention and/or treatment of numerous diseases, including cardiac and circulatory disorders, degenerative disorders of the central nervous system, respiratory disorders, and many diseases for which diuretic treatment is suitable.
• 2-aminopyridine compounds to exhibit adenosine receptor antagonism are known (WO 02/14282, WO 01/25210, etc.), and some 2-aminopyrimidine compounds are also known (WO 03/035639, U.S. 2001/0027196, etc.).
• the present invention relates to a novel pyrazine derivative and a pharmaceutically acceptable salt thereof, which are useful as medicaments; processes for preparing the preparation of pyrazine derivative and a salt thereof; a pharmaceutical composition comprising, as an active ingredient, said pyrazine derivative or a pharmaceutically acceptable salt thereof; a use of said pyrazine derivative or a pharmaceutically acceptable salt thereof as a medicament; and a method for using said pyrazine derivative or a pharmaceutically acceptable salt thereof for therapeutic purposes, which comprises administering said pyrazine derivative or a pharmaceutically acceptable salt thereof to a human being or an animal.
• the pyrazine derivatives and a salt thereof are adenosine antagonists (especially, A 1 receptor and A 2 (particularly A 2a ) receptor dual antagonists) and possess various pharmacological actions such as anticatalepsy action, cognitive enhancing action, analgesic action, locomotor action, antidepressant action, diuretic action, cardioprotective action, cardiotonic action, vasodilating action (e.g.
• cognitive enhancer useful as cognitive enhancer, antianxietry drug, antidementia drug, psychostimulant, analgesic, cardioprotective agent, antidepressant, ameliorants of cerebral circulation, tranquilizer, drug for heart failure, cardiotonic agent, antihypertensive agent, drug for renal failure (renal insufficiency), drug for renal toxicity, renal protective agent, drug for improvement of renal function, diuretic, drug for edema, antiobesity, antiasthmatic, bronchodilator, drug for apnea, drug for gout, drug for hyperuricemia, drug for sudden infant death syndrome (SIDS), ameliorants of immunosuppressive action of adenosine, antidiabetic agent, drug for ulcer, drug for pancreatitis, drug for Meniere's syndrome, drug for anemia; drug for thrombosis, drug for myocardial infarction, drug for obstruction, drug for arteriosclerosis obliterans, drug for thrombophle
• ischemia/reperfusion injury e.g. myocardial ischemia/reperfusion injury, cerebral ischemia/reperfusion injury, peripheral ischemia/reperfusion injury, etc.
• shock e.g.
• endotoxin shock hemorrhagic shock, etc.
• surgical procedure or the like; post-resuscitation asystole; bradyarrhythmia; electromechanical dissociation; hemodynamic collapse; SIRS (systemic inflammatory response syndrome); multiple organ failure; renal failure (renal insufficiency) (e.g. acute renal failure, etc.), renal toxicity [e.g. renal toxicity induced by a drug such as cisplatins, gentamicin, FR-900506 (disclosed in EP-0184162), cyclosporine (e.g.
• cyclosporin A or the like; glycerol, etc.] nephrosis, nephritis, edema (e.g. cardiac edema, nephrotic edema, hepatic edema, idiopathic edema, drug edema, acute angioneurotic edema, hereditary angioneurotic edema, carcinomatous ascites, gestational edema, etc.); obesity, bronchial asthma, gout, hyperuricemia, sudden infant death syndrome, immunosuppression, diabetes, ulcer such as peptic ulcer (e.g.
• pancreatitis Meniere's syndrome, anemia, dialysis-induced hypotension, constipation, ischemic bowel disease, ileus (e.g. mechanical ileus, adynamic ileus, etc.); and myocardial infarction, thrombosis (e.g. arterial thrombosis, cerebral thrombosis, etc.), obstruction, arteriosclerosis obliterans, thrombophlebitis, cerebral infarction, transient ischemic attack, angina pectoris, or the like.
• thrombosis e.g. arterial thrombosis, cerebral thrombosis, etc.
• obstruction arteriosclerosis obliterans
• thrombophlebitis thrombophlebitis
• cerebral infarction transient ischemic attack
• angina pectoris or the like.
• novel pyrazine derivative or a salt thereof of the present invention can be shown by the following formula (I):
• the object compound (I) and a salt thereof of the present invention can be prepared by the following processes.
• the starting compounds or a salt thereof is novel and can be prepared, for example, by the following reaction schemes.
• the object compound (I) and a salt thereof can be prepared, for example, according to the procedures as illustrated in Examples in the present specification or in a manner similar thereto.
• the starting compounds can be prepared, for example, according to the procedures as illustrated in Preparations in the present specification or in a manner similar thereto.
• the object compound (I) and a salt thereof can be prepared according to the methods as shown in Preparations or Examples, or in a manner similar thereto.
• Suitable salts of the object compound (I) are conventional pharmaceutically acceptable ones and include a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt, etc.), an organic acid salt (e.g.
• a metal salt such as an alkali metal salt (e.g. sodium salt, potassium salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (e.g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N′-dibenzylethylenedi
• an inorganic acid salt e.g. hydrochloride, hydrobromide, hydriodide, sulfate, phosphate, etc.
• a salt with an amino acid e.g. arginine, aspartic acid, glutamic acid, etc.
• Suitable “lower alkyl” and “lower alkyl” moiety in the term of “lower alkylthio” and “mono- or di-(lower) alkylamino” may include straight or branched ones such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl or the like, in which the preferred one may be methyl, ethyl or isopropyl.
• Suitable “optionally substituted lower alkyl” may include lower alkyl which is optionally substituted by suitable substituent(s) such as halogen, lower alkenyl, lower alkoxy, hydroxy, cyclo(lower)alkyl, optionally substituted amino, acylamino, aryl, heterocyclic group, acyl or the like, in which the preferred one may be hydroxymethyl, hydroxyethyl, aminoethyl, benzyl or pyridylmethyl.
• suitable substituent(s) such as halogen, lower alkenyl, lower alkoxy, hydroxy, cyclo(lower)alkyl, optionally substituted amino, acylamino, aryl, heterocyclic group, acyl or the like, in which the preferred one may be hydroxymethyl, hydroxyethyl, aminoethyl, benzyl or pyridylmethyl.
• Suitable “lower alkenyl” may include straight or branched ones such as vinyl, propenyl, allyl, isopropenyl, butenyl, pentenyl, hexenyl or the like, in which the preferred one may be vinyl.
• Suitable “optionally substituted lower alkenyl” may include lower alkenyl which is optionally substituted by suitable substituent(s) such as lower alkoxy, hydroxy, cyclo(lower)alkyl, amino, aryl, heterocyclic group, acyl or the like.
• Suitable “lower alkynyl” may include straight or branched ones such as ethynyl, propynyl, butynyl, pentynyl, hexynyl or the like, in which the preferred one may be ethynyl.
• Suitable “optionally substituted lower alkynyl” may include lower alkynyl which is optionally substituted by suitable substituent(s) such as lower alkoxy, hydroxy, cyclo(lower)alkyl, amino, aryl, heterocyclic group, acyl or the like.
• Suitable “lower alkoxy” may include straight or branched ones such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy or the like, in which the preferred one may be (C 1 -C 4 )alkoxy and the more preferred one may be methoxy or ethoxy.
• Suitable “optionally substituted lower alkoxy” may include lower alkoxy which is optionally substituted by suitable substituent(s) such as hydroxy, halogen, cyclo(lower)alkyl, lower alkoxy, optionally substituted amino, optionally substituted aryl, heterocyclic group, acyl or the like.
• Suitable “cyclo(lower)alkyl” may be cyclo(C 3 -C 8 )alkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or the like, in which the preferred one may be cyclohexyl.
• Suitable “aryl” and “aryl” moiety in the terms of “aryloxy” and “arylthio” may include phenyl, naphthyl, indenyl, anthryl, or the like, in which the preferred one may be (C 6 -C 10 ) aryl, and the more preferred one may be phenyl.
• Suitable “optionally substituted aryl” may include aryl which is optionally substituted by suitable substituent(s), preferably 1 to 3 substituent(s), such as lower alkyl, lower alkoxy, hydroxy, halogen, etc.
• suitable substituent(s) preferably 1 to 3 substituent(s)
• suitable substituent(s) such as lower alkyl, lower alkoxy, hydroxy, halogen, etc.
• Suitable examples of optionally substituted aryl include lower alkylphenyl, lower alkoxyphenyl and halophenyl, in which more preferred one is methoxyphenyl or fluorophenyl.
• Suitable “heterocyclic group” may be saturated or unsaturated monocyclic or polycyclic heterocyclic groups containing at least one heteroatom selected from among oxygen, sulfur and nitrogen.
• the particularly preferred example of said heterocyclic group may include
• Suitable “optionally substituted heterocyclic group” may include heterocyclic group which is optionally substituted by suitable substituent(s), preferably 1 to 3 substituent (s), such as lower alkyl, lower alkoxy, hydroxy, oxo, halogen, benzyl, optionally substituted amino, aryl, or the like.
• heteroaryl and “heteroaryl” moiety in the term of “heteroaryl(lower)alkyl” may be aforesaid “heterocyclic group”, in which those categorized as an aromatic heterocyclic group, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, dihydrotriazinyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridyl, tetrazolopyridazinyl, dihydrotriazolopyridazinyl, oxazolyl, isoxazolyl, oxadia
• Suitable “acyl” may include lower alkanoyl, aroyl, carboxy, protected carboxy, and the like.
• Suitable examples of aforesaid “lower alkanoyl” may be formyl, acetyl, propionyl, butyryl, isobutyryl, pivaloyl, hexanoyl, lower(alkyl)sulfinyl (e.g., ethylsulfinyl, etc.), or the like, in which the preferred one may be (C 1 -C 4 )alkanoyl.
• Suitable examples of aforesaid “aroyl” may be benzoyl, toluoyl, or the like.
• Suitable “halogen” may be fluoro, chloro, bromo and iodo.
• Suitable “a leaving group” may include halogen, hydroxy, acyloxy such as alkanoyloxy (e.g. acetoxy, propionyloxy, etc.) or sulfonyloxy (e.g. mesyloxy, tosyloxy, etc.), or the like.
• Suitable “optionally substituted amino” may include amino, mono- or di-(lower)alkylamino (e.g. methylamino, dimethylamino, methylethylamino, etc.), optionally substituted lower alkyl amino (e.g. methoxyethylamino, dimethylaminoethylamino, benzylamino, morphorinoethylamino, pyridylmethylamino, furylmethylamino, etc.) acylamino (e.g. formylamino, lower alkoxycarbonylamino (e.g.
• methoxycarbonylamino, ethoxycarbonylamino, etc. methoxycarbonylamino, ethoxycarbonylamino, etc.
• sulfonylamino e.g. mesylamino, etc.
• ureido ureido, etc.
• methyleneamino (dimethylamino)methyleneamino, dimethylsulfanylideneamino, or the like.
• the compound (Ia) or a salt thereof can be prepared by subjecting the compound (II) or a salt thereof to re-ring-conformation with ammonium acetate following the ring-opening reaction with an acid.
• This reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, 1,2-dimethoxyethane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, N,N-dimethylformamide, methanol, ethanol, dimethyl sulfoxide, diethyl ether, ethyl acetate, a mixture thereof or any other organic solvent which does not adversely affect the reaction.
• a conventional solvent such as water, acetone, dioxane, acetonitrile, 1,2-dimethoxyethane, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, N,N-dimethylformamide, methanol, ethanol, dimethyl sulfoxide, diethyl ether, ethyl acetate, a mixture thereof or any other organic solvent which does not adversely affect the reaction.
• the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or heating.
• the compound (Ib) or a salt thereof can be prepared by subjecting the compound (III) or a salt thereof to ring-conformation with ammonium acetate.
• the reaction may be carried out in a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene dichloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely affect the reaction.
• a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene dichloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely affect the reaction.
• alcohol e.g. methanol, ethanol, etc.
• acetone e.g. acetone
• dioxane aceton
• the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under heating.
• the compound (Ic) or a salt thereof can be prepared by one pot reaction consisting of in situ rearrangement-amination following the alkylation of hydroxyl-oxygen atom of the compound (Ia) or a salt thereof with iodoacetamide.
• the present reaction may be carried out in a solvent such as water, phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene dichloride, formamide, N,N-dimethylformamide, methanol, ethanol, sec-butanol, amyl alcohol, diethyl ether, dioxane, tetrahydrofuran, dimethyl sulfoxide, or any other organic solvent, which does not adversely affect the reaction, preferably in ones having strong polarities.
• a solvent such as water, phosphate buffer, acetone, chloroform, acetonitrile, nitrobenzene, methylene chloride, ethylene dichloride, formamide, N,N-dimethylformamide, methanol, ethanol, sec-butanol, amyl alcohol, diethyl ether, dioxane, tetrahydrofuran, dimethyl sulfoxide, or any other organic solvent
• the reaction is preferably conducted in the presence of base, for example, inorganic base such as alkali metal hydroxide, alkalimetal carbonate, alkalimetal bicarbonate, alkali metal hydride (e.g. sodium hydride, etc.), organic base such as trialkylamine, and the like.
• inorganic base such as alkali metal hydroxide, alkalimetal carbonate, alkalimetal bicarbonate, alkali metal hydride (e.g. sodium hydride, etc.), organic base such as trialkylamine, and the like.
• the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under heating.
• the present reaction is preferably carried out in the presence of alkali metal halide (e.g. sodium iodide, potassium iodide, etc.), alkali metal thiocyanate (e.g. sodium thiocyanate, potassium thiocyanate, etc.), di(lower)alkyl azodicarboxylate (e.g. diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.) or the like.
• alkali metal halide e.g. sodium iodide, potassium iodide, etc.
• alkali metal thiocyanate e.g. sodium thiocyanate, potassium thiocyanate, etc.
• di(lower)alkyl azodicarboxylate e.g. diethyl azodicarboxylate, diisopropyl azodicarboxylate, etc.
• This reaction can be carried out by the method disclosed in Example 3 and 31, etc. mentioned later or the similar manners thereto.
• the compound (Ie) or a salt thereof can be prepared by reacting the compound (Id) or a salt thereof with the compound (IV) or a salt thereof.
• This reaction can be carried out by the method disclosed in Example 32, etc. mentioned later or the similar manners thereto.
• the compound (If) or a salt thereof can be prepared by subjecting the compound (V) or a salt thereof to pyrazine ring-formation with 2,3-diamino-2-butenedinitrile.
• the reactions may be carried out in a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene dichloride, tetrahydrofuran, ethyl acetate, toluene, N,N-dimethylformamide, dimethyl sulfoxide, pyridine or any other organic solvent which does not adversely affect the reaction.
• a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene dichloride, tetrahydrofuran, ethyl acetate, toluene, N,N-dimethylformamide, dimethyl sulfoxide, pyridine or any other organic solvent which does not adversely affect the reaction.
• alcohol e.g. methanol,
• the reaction is preferably conducted in the presence of a base or an acid.
• Suitable base includes an inorganic base and organic base such as an alkali metal (e.g. sodium, potassium, etc.), an alkaline earth metal (e.g. magnesium, calcium, etc.), the hydroxide or carbonate or bicarbonate or hydride or alkoxide thereof, trialkylamine (e.g. trimethylamine, triethylamine, etc.), hydrazine, picoline, or the like.
• alkali metal e.g. sodium, potassium, etc.
• an alkaline earth metal e.g. magnesium, calcium, etc.
• trialkylamine e.g. trimethylamine, triethylamine, etc.
• hydrazine picoline, or the like.
• Suitable acid includes an inorganic acid and organic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, or the like.
• the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under heating.
• This reaction can be carried out by the method disclosed in Example 4, etc. mentioned later or the similar manners thereto.
• the compound (Ic) or a salt thereof can be prepared by subjecting the compound (Ig) to substitution with aqueous ammonia.
• the reactions may be carried out in a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, dioxane, or any other solvent which is easy to mix with water and does not adversely affect the reaction.
• a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetone, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, dioxane, or any other solvent which is easy to mix with water and does not adversely affect the reaction.
• the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under heating.
• This reaction can be carried out by the method disclosed in Example 21 mentioned later or the similar manners thereto.
• the compound (Ih) or a salt thereof can be prepared by subjecting the compound (Ig) or a salt thereof to nucleophilic substitution with an amine such as the compound (VI) or a salt thereof.
• the reactions may be carried out in a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetamide, dimethyl acetamide, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, dioxane, or any other solvent which does not adversely affect the reaction.
• a conventional solvent such as water, alcohol (e.g. methanol, ethanol, etc.), acetamide, dimethyl acetamide, N,N-dimethylformamide, tetrahydrofuran, acetonitrile, dioxane, or any other solvent which does not adversely affect the reaction.
• a liquid amine can be also used as the solvent.
• the reaction temperature is not critical, and the reaction is usually carried out at ambient temperature, under warming or under heating.
• This reaction can be carried out by the method disclosed in Example 5 mentioned later or the similar manners thereto.
• the compound (Ic) or a salt thereof can be prepared by subjecting the compound (Ih) or a salt thereof to deprotection of amino using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
• the reaction is usually carried out in a solvent such as water, an alcohol (e.g. methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, or any other organic solvent which does not adversely affect the reaction, or a mixture thereof.
• a solvent such as water, an alcohol (e.g. methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, or any other organic solvent which does not adversely affect the reaction, or a mixture thereof.
• a solvent such as water, an alcohol (e.g. methanol, ethanol, isopropy
• the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
• This reaction can be carried out by the method disclosed in Example 6 mentioned later or the similar manners thereto.
• the compound (Ii) or a salt thereof can be prepared by subjecting the compound (VII) or a salt thereof coupling reaction with the organoboron compound (VIII) or a salt thereof.
• the present reaction is preferably carried out by the method disclosed in Example 200 and 201 mentioned later or the similar manner thereto.
• the compound (Ic) or a salt thereof can be prepared from the compound (Ii) by hydrolysis.
• the hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.
• Suitable base includes an inorganic base and organic base such as an alkali metal (e.g. sodium, potassium, etc.), an alkaline earth metal (e.g. magnesium, calcium, etc.), the hydroxide or carbonate or bicarbonate thereof, trialkylamine (e.g. trimethylamine, triethylamine, etc.), hydrazine, picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 4,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, or the like.
• alkali metal e.g. sodium, potassium, etc.
• an alkaline earth metal e.g. magnesium, calcium, etc.
• trialkylamine e.g. trimethylamine, triethylamine, etc.
• hydrazine picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 4,4-d
• Suitable acid includes an organic acid (e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.), an inorganic acid (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.) and Lewis acid (e.g. boron tribromide, boron trichloride, boron trifluoride, aluminum chloride, titanium trichloride, etc.).
• organic acid e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.
• an inorganic acid e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.
• Lewis acid e.g. boron tribromide, boron trichloride, boron trifluoride, aluminum chloride, titanium trichloride
• the reaction is usually carried out in a solvent such as water, an alcohol (e.g. methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, or any other organic solvent which does not adversely affect the reaction, or a mixture thereof.
• a solvent such as water, an alcohol (e.g. methanol, ethanol, isopropyl alcohol, etc.), tetrahydrofuran, dioxane, toluene, methylene chloride, ethylene dichloride, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, or any other organic solvent which does not adversely affect the reaction, or a mixture thereof.
• a solvent such as water, an alcohol (e.g. methanol, ethanol, isopropy
• a liquid base or acid can be also used as the solvent.
• the reaction temperature is not critical and the reaction is usually carried out under cooling to heating.
• This reaction can be carried out by the method disclosed in Example 41 mentioned later or the similar manners thereto.
• the compound (Ij) or a salt thereof can be prepared by subjecting the compound (If) or a salt thereof coupling reaction with the organoboron compound (IX) or a salt thereof.
• the present reaction is preferably carried out by the method disclosed in Example 78 mentioned later or the similar manner thereto.
• the compound (Im) or a salt thereof can be prepared by subjecting the compound (Ik) or a salt thereof coupling reaction with the compound (X) or a salt thereof.
• the present reaction is preferably carried out by the method disclosed in Examination 69 mentioned later or the similar manner thereto.
• the compound (XII) or a salt thereof can be prepared by subjecting the compound (XI) to the oxime-formation reaction (exemplified by Step 1) by the methods disclosed in Preparation 1 and 2 mentioned later or the similar manners thereto.
• the compound (XV) can be synthesized by functional trans-formation reaction of the oxime, which is the method disclosed in Preparation 3, 4, 5 and 6 mentioned later or the similar manners thereto that is obvious to the person skilled in the organic chemistry, from the compound (XII).
• Step 5 of this process can be carried out by the method disclosed in Preparation 7 mentioned later or the similar manners thereto.
• the object compound (IIa) or a salt thereof can be prepared by subjecting the compound (XVI) or a salt thereof to the alkylation (exemplified by Step 6). This reaction is carried out in the method disclosed in Preparation 8 and 9 mentioned later or the similar manners thereto.
• the another object compound (IIb) can be prepared by subjecting the compound (IIa) to the hydrolysis (exemplified by Step 7) that is disclosed in Preparation 10 mentioned later or the similar manners thereto.
• the compound (XVIII) or a salt thereof can be prepared by subjecting the compound (XVII) or a salt thereof to the alkylation (exemplified by Step 1). This reaction is carried out in the method disclosed in Preparation 12 and 14 mentioned later or the similar manners thereto.
• the object compound (V) or a salt thereof can be prepared by subjecting the compound (XVIII) to oxidation (exemplified by Step 2), which is disclosed in Preparation 11, for example, mentioned later or the similar manners thereto.
• the compound (III) or a salt thereof can be prepared by reacting the compound (XIX) or a salt thereof with the compound (XX) or a salt thereof. This reaction can be carried out by the method disclosed in Preparation 17 mentioned later or the similar manners thereto.
• the compound (XXII) can be prepared by subjecting the compound (XXI) to the oxime-formation reaction (exemplified by Step 1) that disclosed in Preparation 20 mentioned later or the similar manners thereto.
• the compound (XXIII) or a salt thereof can be prepared by reacting the compound (XXII) or a salt thereof with aminomalonitrile.
• the present reaction is preferably carried out by the method disclosed in Preparation 21 mentioned later or the similar manner thereto.
• the object compound (VII) or a salt thereof can be carried out by reacting the compound (XXIII) or a salt thereof with phosphorus oxychloride. This reaction can be carried out by the method disclosed in Preparation 22 mentioned later or the similar manner thereto.
• all starting materials and product compounds may be salts.
• the compounds of above processes can be converted to salts according to a conventional method.
• the object compound (I) of the present invention is an adenosine antagonist and possesses the various pharmacological actions as stated before.
• the adenosine antagonistic activity [Ki (nM)] of the test compound was examined by radioligand binding techniques using 8-cyclopentyl-1,3-dipropylxanthine, [dipropyl-2,3- 3 H(N)] ([ 3 H]DPCPX, 4.5 nM) for human A 1 receptor and [ 3 H]CGS 21680 (20 nM) for human A 2a receptor.
• the pyrazine compound (I) and a salt thereof of this invention are useful as adenosine antagonists (especially, A 1 receptor and A 2 (particularly A 2a ) receptor dual antagonists) and for the prevention and/or the treatment of depression, dementia (e.g.
• Adenosine antagonists can be useful for Parkinson's disease by co-administrating with L-3,4-dihidroxy-phenylalanine (L-DOPA), which is the most popular drug for Parkinson's disease (R. Grondin et. al, Neurology , 52, 1673-1677 (1999)). So the combination use of the pyrazine compound (I) and a salt thereof of this invention with L-DOPA may be also useful for treatment and/or prevention of Parkinson's disease with decreasing or reducing the side effect such as the onset of dyskinesia eliciting by the long-team application of L-DOPA, and so on.
• L-DOPA L-3,4-dihidroxy-phenylalanine
• these compounds should be durable to some degree. And the duration time of the pyrazine compound (I) or a salt thereof of this invention are expected to be long-lasting.
• the pharmaceutical composition of this invention can be used in the form of a pharmaceutical preparation, for example, in a solid, semisolid or liquid form, which contains the pyrazine compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation.
• a pharmaceutical preparation for example, in a solid, semisolid or liquid form, which contains the pyrazine compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient in admixture with an organic or inorganic carrier or excipient suitable for rectal, pulmonary (nasal or buccal inhalation), nasal, ocular, external (topical), oral or parenteral (including subcutaneous, intravenous and intramuscular) administrations or insufflation.
• the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, troches, capsules, suppositories, creams, ointments, aerosols, powders for insufflation, solutions, emulsions, suspensions, and any other form suitable for use.
• auxiliary, stabilizing agents, thickening agents, coloring agents and perfumes may be used where necessary.
• the pyrazine compound (I) or a pharmaceutically acceptable salt thereof is included in a pharmaceutical composition in an amount sufficient to produce the desired aforesaid pharmaceutical effect upon the process or condition of diseases.
• the composition For applying the composition to a human being or an animal, it is preferable to apply it by intravenous, intramuscular, pulmonary or oral administration, or insufflation. While the dosage of therapeutically effective amount of the pyrazine compound (I) varies depending on the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.01-100 mg of the pyrazine compound (I) per kg weight of a human being or an animal, in the case of intramuscular administration, a daily dose of 0.1-100 mg of the pyrazine compound (I) per kg weight of a human being or an animal, and in case of oral administration, a daily dose of 0.1-100 mg of the pyrazine compound (I) per kg weight of a human being or an animal is generally given for the prevention and/or treatment of the aforesaid diseases.
• 2-isopropyl-6-(2-oxo-2-phenylethyl)-3(2H)-pyridazinone 513 mg was added to a suspension of NaH (60% dispersion in mineral oil) (84 mg) in THF (5 ml) and the mixture was stirred at 45-50° C. for 30 minutes. After addition of isoamyl nitrite (0.27 ml), the mixture was stirred at the same temperature for 8 hours. The mixture was dissolved in EtOAc, washed with 1N HCl and brine and dried over MgSO 4 .
• Zinc dust (1.57 g) was added in portions to a suspension of 1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-phenyl-1,2-ethanedione 1-oxime (856 mg) in a mixture acetic anhydride (1.7 ml) and AcOH (10 ml) under ambient temperature and the mixture was stirred at the same temperature for 4 hours. An insoluble material was filtered off and a filtrate was concentrated under reduced pressure to give a residue. The residue was dissolved in EtOAc, washed with sat. aq.
• 6-(phenylethynyl)-3(2H)-pyridazinone (15.54 g) was added to a suspension of NaH (60% in oil suspension) (3.33 g) in DMF (90 ml) and the mixture was stirred at 50-55° C. for 30 minutes. Under ice-cooling, iodoethane (6.97 ml) was added to the mixture and the mixture was stirred at 50-55° C. for 3 hours. After addition of water, the reaction mixture was extracted with EtOAc, dried over MgSO 4 and concentrated under reduced pressure to give a residue.
• iodomethane (0.6 ml) was added to a solution of 6-[5-amino-3-phenyl-6-(4-pyridyl)-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (120 mg) in THF (3 ml) and the mixture was stirred at 25-35° C. for 18 hours. A precipitate was collected by filtration to give 4-[3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinyl]-1-methylpyridinium iodide (152 mg).
• Potassium carbonate (77 mg) was added to a solution of 6-(5-hydroxy-6-methyl-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (150 mg) and iodoacetamide (95 mg) in DMA (1 ml) and the mixture was stirred at 20-25° C. for 2 hours.
• potassium carbonate (235 mg) was added and heated at 150-155° C. for 2 hours. After addition of water, the mixture was extracted with CHCl 3 , washed with brine, dried over MgSO 4 and concentrated under reduced pressure to give a residue.
• reaction mixture was concentrated under reduced pressure and subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (60:40 v/v) to give 5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-6-phenyl-2,3-pyrazinedicarbonitrile as a solid (1.30 g).
• a less polar one is 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarbonitrile (350 mg) and a more polar one is 3-amino-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-6-phenyl-2-pyrazinecarbonitrile (51 mg).
• the precipitate was purified by column chromatography on silica gel (EtOAc only) to give a solid.
• the solid was crystallized from a mixture of n-hexane and CHCl 3 to give 3-[bis(4-methoxybenzyl)amino]-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarbonitrile (16.58 g).
• N-bromosuccinimide (875 mg) was added to a solution of 6-(5-amino-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (1.51 g) in DMF (15 ml). The mixture was stirred at 50-55° C. for one hour and poured into water (150 ml). The precipitate was collected by filtration, dissolved in CHCl 3 , dried over MgSO 4 and concentrated under reduced pressure to give a solid.
• m-chloroperbenzoic acid 70-75% purity (530 mg) was added to a mixture of 6-[5-amino-6-(methylsulfinyl)-3-phenyl-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (750 mg) in CH 2 Cl 2 (7.5 ml). The mixture was stirred at 25-30° C. for 5 hours, washed with saturated aq. sodium thiosulfate, saturated aq. NaHCO 3 and brine, dried over MgSO 4 and concentrated under reduced pressure to give a residue.
• Example 55 The title compounds were obtained in a similar manner to that of Example 55.
• triethylamine 0.97 ml was dropwise added to a mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (1.00 g) and ethynyl(trimethyl)silane (0.716 ml) in 1,2-dichloroethane (20 ml) under ice-cooling. The mixture was stirred at same temperature for one hour and at 25-30° C. for 18 hours.
• triethylamine (0.0794 ml) was dropwise added to a mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (200 mg) and ethynylbenzene (0.0626 ml) in 1,2-dichloroethane (2 ml) at 60° C. The mixture was refluxed for 2 hours. The mixture was cooled to give a precipitate.
• triethylamine 0.1192 ml was dropwise added to a mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (300 mg) and ethynyl(trimethyl)silane (85.6 mg) in 1,2-dichloroethane (3 ml) at 60° C. The mixture was refluxed for 2 hours. After addition of water, an organic layer was collected, washed with sat. aq.
• triethylamine (0.0596 ml) was dropwise added to a mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (150 mg) and 2-ethynylpyridine (0.0431 ml) in 1,2-dichloroethane (1.5 ml) at 30-35° C. The mixture was stirred at the same temperature for 18 hours. Water was added to the reaction mixture to give a solid.
• the solid was purified by column chromatography on silica gel (EtOAc only) to give a solid.
• the solid was suspended in acetone to give 6-[5-amino-3-phenyl-6-(2-pyridylethynyl)-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone (88 mg).
• triethylamine (0.0596 ml) was dropwise added to a mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (150 mg) and 5-ethynyl-1-methyl-1H-imidazole (45.4 mg) in THF (1.5 ml) at 50° C. The mixture was refluxed for 2 hours. Water was added to the reaction mixture to give a solid.
• triethylamine (0.0685 ml) was dropwise added to a mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-methyl-3(2H)-pyridazinone (150 mg) and ethynylbenzene (0.0054 ml) in DMF (1.5 ml) at 75-80° C. The mixture was stirred at the same temperature for 2 hours. To the reaction mixture, water was added to give a solid.
• the solid was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (40:60 v/v) to give a solid.
• the solid was suspended in acetone to give 6-[5-amino-3-phenyl-6-(phenylethynyl)-2-pyrazinyl]-2-methyl-3(2H)-pyridazinone (96 mg).
• 6-[5-amino-3-phenyl-6-(1H-pyrazol-4-yl)-2-pyrazinyl]-2-isopropyl-3(2H)-pyridazinone 120 mg was added to a suspension of NaH (60% in oil) (14.2 mg) and the mixture was stirred at 25-30° C. for 30 minutes. The mixture was cooled in an ice bath and iodomethane (0.1 ml) was added. The mixture was stirred at the same time for 30 minutes and at 20-30° C. for one hour. After addition of water (3.6 ml), a precipitate was collected by filtration and purified by column chromatography on silica gel (EtOAc only) to give a solid.
• the syrup was purified by column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (50:50 v/v) to give a solid.
• the solid was suspended in acetone and collected by filtration to give 6-(6-acetyl-5-amino-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (28 mg).

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